I. RORalpha and gamma: The retinoid-related orphan receptor a and g (RORa and RORc) are members of the nuclear receptor superfamily. To identify the physiological functions of RORa and c, mice deficient in RORa and c function were analyzed. RORc exhibit several functions in the immune system. RORc expression is indispensable for lymph node organogenesis and plays a critical role in thymocyte homeostasis. Recently a role for RORc in Th17 cell differentiation was identified. We demonstrated that both RORa and RORc are induced during Th17 cells differentiation and double knockouts mice are resistant to experimental autoimmune encephalomyelitis, a model for multiple sclerosis. In addition, RORc-deficient mice are less susceptible to ovalbumin (OVA)-induced inflammation in mice, a model for allergic airway disease. This led to the concept that RORc antagonists may be useful in the therapy of various autoimmune diseases. A series of RORc antagonists were shown to inhibit the activation of the IL-17 promoter and reverse the phenotypic effects associated with psoriasis suggesting that they may be useful in the treatment of this disease. In addition a relationship has been found between decreased level of ROR expression and increased malignancy of melanoma. Recently, we also showed that also a number of vitamin D metabolites can interact with RORa and RORc and can function as inverse agonists thereby identifying an alternative mechanism by which vitamin D can mediate its physiological functions. Retinoid-related orphan receptors alpha (RORa) and gamma (RORg) are both expressed in liver and adipose tissue and play a role in the regulation of lipid and glucose metabolism as well as the control of metabolic syndrome. RORa and RORc receptors influence the regulation of several metabolic pathways, including those involved in the metabolism of steroids, bile acids, and xenobiotics, suggesting that RORs are important in the control of metabolic homeostasis. RORa plays an important role in the regulation of energy homeostasis. Mice deficient in RORa are resistant to diet-induced obesity and reduced inflammation in adipose tissue. A number of lipogenic genes were identified that are directly regulated by RORa. Mice deficient in RORc also have a reduced susceptibility to develop insulin resistance and become glucose intolerant. Because RORs function as ligand-dependent transcription factors, RORa might be a therapeutic target for the management of obesity. Our studies further identified Prox1 as a novel modulator of ROR transcriptional regulation and as such is an integral part of the circadian clock and metabolic regulatory networks. RORc participates in the diurnal regulation of several glucose and lipid metabolic genes and regulates insulin sensitivity. ChIp-Seq analysis showed that RORc is recruited to the regulatory region of a number of glucose and lipid metabolic genes suggesting that RORc regulates these directly. II. JAZF1/TIP27: This nuclear protein interacts with the nuclear orphan receptor TAK1 and functions as a regulator of transcription; however little is know about factors mediating its activity. Generation of TAK1 and JAZF1 KO mice revealed several phenotypes that are currently being investigated. Both TAK1 and JAZF1play a role in the regulation of energy homeostasis. Mice deficient in TAK1 or JAZF1 are protected against the development of obesity, hepatic steatosis, and insulin resistance. A number of lipid and glucose metabolic genes were identified that are regulated by TAK1 and JAZF1. The JAZF1 signaling pathway might provide an additional therapeutic target to interfere in metabolic syndrome.